The heterogeneity of Alzheimer's disease (AD) is a source of difficulty in the analysis of its causes and treatment. Heterogeneity is suggested in genetic causes of AD by the contrast between familial and "sporadic" cases and, within familial disease, by the tendency of age at onset to "run true" within families. Heterogeneity in the neuropathology of AD is also apparent, since earlier-onset cases show cell loss in brain stem nuclei including the locus coeruleus and the dorsal raphe nuclei. The clinical heterogeneity of AD is also well known: cases vary not only in age at onset and rate of progression but also in their tendency to show prominent symptoms of depression. We shall investigate the interrelationships among these aspects of heterogeneity in AD as well a their relationship to an additional variable, the heritable tendency toward depression as revealed by patients' past psychiatric histories and family histories of major affective illness. Index cases will comprise a sequential series of 150 subjects with Alzheimer's disease diagnosed clinically with autopsy confirmation, whose brains have been forwarded to the brain bank/neuropathology core of the Bryan ADRC. Neuropathologic investigations, medical records, and detailed information from interviews with multiple family members will be used to test the following central hypothesis: the tendency toward depression in AD is inherited. The trait in question is revealed by a history of depression before the onset of dementia, and by a family history of affective disorder. This same trait results in early onset of symptoms and involvement of the locus coeruleus, serotonergic midbrain nuclei, or both during the pathologic process of AD. This involvement in turn results in symptoms of depression along with dementia. Therefore, clinical, neuropathologic and family/genetic investigations of AD cases will show association among family history of affective disorders, age at onset, depressive symptoms (both prior to and concurrent with symptoms of dementia), and neuropathology in the locus coeruleus and/or the dorsal raphe nuclei.